The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
CD73 is a cell-surface enzyme that has 5′-ectonucleotidase activity. It thus mediates the conversion of monophosphorylated purine nucleotides into corresponding nucleosides. For example, dephosphorylation of AMP to adenosine is catalyzed by CD73. CD73 is also present as a soluble form in the plasma and the soluble enzyme has the same enzymatic activity as the membrane bound form.
Adenosine is one of the physiological regulators of endothelial cell permeability [1, 2], and can thus be involved in the pathogenesis of many disorders like acute lung injury, systemic inflammatory response syndrome, acute respiratory distress syndrome, high-altitude sickness. Changes in endothelial permeability also take place in inflammation, in traumas and in cancer. CD73 controls endothelial permeability via an adenosine-mediated mechanism in normal conditions, hypoxia and ventilator-induced lung injury [3-7].
CD73 is induced by certain cytokines. Most importantly, interferon alpha and beta have been reported to increase the expression and activity of CD73 in humans (8, WO 2004/084933, 11). These cytokines are also clinically used to treat different diseases. Interferon alpha, for instance is used to treat certain infections and malignancies such as hepatitis and hairy cell leukemia. Interferon beta, on the other hand, is widely used to dampen inflammation in multiple sclerosis. However, in many cases the beneficial response to interferon treatment is only seen in a subpopulation of patients, and also the initially responding patients can later became refractory to the treatment. Thus, there is a need to develop easily measurable biomarkers that reflect the biological responsiveness of the body to the treatment.
The patent publication WO 2004/084933 discloses the use of cytokines for inducing endothelial CD73 expression and subsequently elevating the adenosine level in an individual. The use of interferon beta in combination with adenosine monophosphate (AMP) in the treatment of multi-organ failure in rats is described.
The patent publication WO 2007/042602 describes the use of plain interferon beta for treatment or prevention of ischemia reperfusion injury or multi-organ failure. Statins, hypolipidemic agents used to lower cholesterol level, are known to induce CD73 expression in the patients.
However, there is no disclosure in prior art concerning measuring CD73 protein in serum or any other tissue fluid for use as a biomarker for monitoring development of diseases or for assessment of efficacy of therapies.